MtDNA as a Mediator for Expression of Hypoxia-Inducible Factor 1? and ROS in Hypoxic Neuroblastoma Cells.

ABSTRACT: Mitochondria consume O? to produce ATP and are critical for adaption of hypoxia, but the role of mitochondria in HIF-1? pathway is as yet unclear. In this study, mitochondrial DNA (mtDNA) enriched (SK-N-AS) and depleted (??) cells of neuroblastoma were cultured in a hypoxic chamber to simulate a hypoxic condition and then the major components involved in mitochondrial related pathways, hypoxia-inducible factor 1? (HIF-1?) and reactive oxygen species (ROS) were measured. The results showed that hypoxia-stimulated exposure elevated expression of HIF-1?, which was additionally influenced by level of generated ROS within the cytosol. Moreover, elevation of HIF-1? also resulted in increases of lactate dehydrogenase A (LDH-A) and pyruvate dehydrogenase kinase 1 (PDK1) in both hypoxic cells. The expression of mitochondrial biogenesis related proteins and metabolic components were noted to increase significantly in hypoxic SK-N-AS cells, indicating that mtDNA was involved in mitochondrial retrograde signaling and metabolic pathways. An analysis of dynamic proteins found elevated levels of HIF-1? causing an increased expression of dynamin-related protein 1 (DRP1) during hypoxia; further, the existence of mtDNA also resulted in higher expression of DRP1 during hypoxia. By using siRNA of HIF-1? or DRP1, expression of DRP1 decreased after suppression of HIF-1?; moreover, the expression of HIF-1? was also affected by the suppression of DRP1. In this study, we demonstrated that mtDNA is a mediator of HIF-1? in eliciting metabolic reprogramming, and mitochondrial biogenesis. Identification of a mutual relationship between HIF-1? and DRP1 may be a critical tool in the future development of clinical applications.

SUBMITTER: Kuo CW 

PROVIDER: S-EPMC5486043 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature